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Introduction: Laryngeal chondrosarcoma (CS) is a rare indolent malignant tumor. High-grade (G3), dedifferentiated (DD), and myxoid (MY) CSs are considered more aggressive subtypes due to their metastatic potential and relatively poor outcomes. The aim of this systematic review is to evaluate treatment modalities and survival outcomes in patients affected by these rarer CS subtypes., Methods: Papers published from January 1, 2000, to August 25, 2024, describing cases of laryngeal G3, DD, and MY CS were included., Results: A total of 38 patients (15 G3, 13 DD, and 10 MY) were selected. Cricoid cartilage was the most common site of origin. Total laryngectomy (TL) was often performed. Primary conservative approaches in 42.8% of patients were followed by loco-regional recurrence., Conclusions: Aggressive subtypes of CS require a radical approach because of the higher rate of loco-regional and distant recurrences compared to low-grade CS. TL with radical intent is the most common treatment, and adjuvant therapy should be considered after careful multidisciplinary discussion., Competing Interests: Declarations. Conflict of Interest: Alfio Ferlito is an Editorial Board member of Oncology and Therapy. Alfio Ferlito was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Cesare Piazza, Claudia Montenegro, Michele Tomasoni, Ilmo Leivo, Göran Stenman, Abbas Agaimy, Roderick H. W. Simpson, and Nina Zidar have nothing to disclose. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

Sclerosing mucoepidermoid carcinoma (SMEC) of the salivary glands is a rare variant of low-grade mucoepidermoid carcinoma with scanty cellular atypia characterized by marked fibrosis/sclerosis and a rich inflammatory infiltrate. Herein, we report 25 unpublished cases of SMEC, two of them with prominent eosinophilia (2/25; 8%) and three with abundant IgG4-positive plasma cells (3/25; 12%). In our series of salivary SMEC, molecular analysis using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) provided evidence of MAML2 gene rearrangement in 18 cases of the 21 analyzable cases tested (86%), while this gene locus was intact in 3 cases (14%). This study focuses on the diagnostic criteria of salivary SMEC given its challenge of abundant collagenous stroma, minimal residual neoplastic areas, and inconspicuous mucous cells. Follow-up data of our cases indicate that salivary SMECs have favorable outcomes. Molecular analysis for MAML2 gene rearrangement suggests that SMECs of salivary glands represent a rare variant of conventional low-grade MECs of salivary glands. In contrast, SMECs of the thyroid gland are genetically distinct from salivary-type thyroid MECs., Competing Interests: Declarations Ethics approval The study was approved by the institutional review board of the Faculty of Medicine in Pilsen, Charles University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Informed consent No patient consent was required for this study. Conflict of interest The authors have no relevant financial or non-financial interests to disclose. AA is the Editor-in-Chief of Virchows Archiv. AS serves on the Editorial Board of Virchows Archiv., (© 2024. The Author(s).)

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic., (© 2024. The Author(s).)

Classification of tumors of the head and neck has evolved in recent decades including a widespread application of molecular testing in tumors of the sinonasal tract, salivary glands, and soft tissues with a predilection for the head and neck. The availability of new molecular techniques has allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, an expanding spectrum of immunohistochemical markers specific to genetic alterations facilitates rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined tumor classification while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review covers the principal molecular alterations in sinonasal malignancies, such as alterations in DEK, AFF2, NUTM1, IDH1-2, and SWI/SNF genes in particular, that are important from a practical standpoint for diagnosis, prognosis, and prediction of response to treatment., (© 2024. The Author(s).)

Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The significant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classification, and better characterization and thereby, looking for new avenues for improving patient outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6 :: NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6 :: NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6 :: NTRK3 and MYB :: SMR3B . Less frequent fusion transcripts included ETV6 :: RET (n=12) and VIM :: RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P <0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6 :: NTRK3 . There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC., Competing Interests: Conflicts of Interest and Source of Funding: This study was in part supported by study grant SVV 260539 from the Ministry of Education, Czech Republic, the Cooperation Program, research area SURG, the project National Institute for Cancer Research—NICR (Programme EXCELES, ID Project No. LX22NPO5102). Funded by the European Union—Next Generation EU and the Finnish Cancer Society, Finska Läkaresällskapet, and Maritza and Reino Salonen Foundation, Finland. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). β-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and β-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This review focuses on the heterogenous group of clear cell neoplasms of salivary glands and attempts to identify major differential diagnostic features. Within the head and neck region, clear cells are found most commonly in salivary gland tumors, but may also be seen in tumors of squamous or odontogenic epithelial origin, primary or metastatic carcinomas, benign or malignant melanocytic lesions, or benign or malignant mesenchymal tumors. Clear cells occur fairly commonly among a wide variety of salivary gland neoplasms, but mostly they constitute only a minor component of the tumor cell population. Clear cells represent a major diagnostic feature in two salivary gland neoplasms, epithelial-myoepithelial carcinoma and hyalinizing clear cell carcinoma. In addition, salivary gland neoplasms composed predominantly of clear cells could also include clear cell variants of other salivary neoplasms, such as mucoepidermoid carcinoma and myoepithelial carcinoma, but their tumor type-specific histologic features may only be available in limited nonclear cell areas of the tumor. Diagnosing predominantly clear cell salivary gland tumors is difficult because the immunoprofiles and morphologic features may overlap and the same tumor entity may also have a wide range of other histologic presentations. Many salivary gland tumors are characterized by tumor type-specific genomic alterations, particularly gene fusions of the ETV6 gene in secretory carcinoma, the MYB and MYBL1 genes in adenoid cystic carcinoma, the MAML2 gene in mucoepidermoid carcinoma, the EWSR1 gene in hyalinizing clear cell carcinoma, and others. Thus, along with conventional histopathologic examination and immunoprofiling, molecular and genetic tests may be important in the diagnosis of salivary gland clear cell tumors by demonstrating genetic alterations specific to them., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This review gives a brief history of the development of head and neck pathology in Europe from a humble beginning in the 1930s to the explosive activities the last 15 years. During the decades before the introduction of immunohistochemistry in the 1980s, head and neck pathology grew as a subspeciality in many European countries. In the late 1940s, the Institute of Laryngology and Otology with its own pathology laboratory was founded in London, and in 1964 the World Health Organization (WHO) International Reference Centre for the Histological Classification of Salivary Tumours was established at the Bland-Sutton Institute of Pathology, also in London. International collaboration, and very much so in Europe, led to the publication of the first WHO Classification of Salivary Gland Tumours in 1972. In the 1960s, a salivary gland register was organised in Hamburg and in Cologne the microlaryngoscopy was invented enabling microscopic endoscopic examination and rather shortly afterwards a carbon dioxide laser attached to the microscope became established and laryngeal lesions could be treated by laser vaporisation. During the last three decades, the use of immunohistochemistry supplemented with cytogenetic and refined molecular techniques has greatly facilitated the pathological diagnostics of head and neck lesions and has had a huge impact on research. Collaboration between different European centres has drastically increased partly due to establishment of scientific societies such as the Head and Neck Working Group (HNWG) within the European Society of Pathology and the International Head and Neck Scientific Group (IHNSG). A very large number of European pathologists have contributed to the 2nd, 3rd and 4th WHO books, and are involved in the upcoming 5th edition. Accredited educational meetings and courses are nowadays regularly arranged in Europe. Numerous textbooks on head and neck pathology have been written and edited by European pathologists. The increased collaboration has created larger series of tumours for research and new entities, mainly defined by their genetic abnormalities, are continuously emerging from Europe, particularly regarding salivary gland neoplasms and "undifferentiated" sinonasal tumours. These findings have led to a better and more precise classification and open the possibilities for new treatment strategies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements., Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction., Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts., Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.

Background: Adenoid cystic carcinoma (ACC) is a slow growing salivary gland malignancy that is molecularly characterized by t(6:9)(q22-23;p23-24) translocations which predominantly result in MYB-NFIB gene fusions in nearly half of tumours. Detection of MYB-NFIB transcripts is typically performed with fresh ACC tissue using conventional RT-PCR fragment analysis or FISH techniques, which are prone to failure when only archival formalin fixed paraffin embedded (FFPE) tissue is available. The purpose of this pilot study was to evaluate the utility of NanoString probe technology for the detection of MYB-NFIB transcripts in archival ACC tissue., Methods: A NanoString probeset panel was designed targeting the junctions of three currently annotated MYB-NFIB fusion genes as well as 5'/3' MYB probesets designed to detect MYB gene expression imbalance. RNA isolated from twenty-five archival ACC specimens was profiled and analyzed. RT-qPCR and sequencing were performed to confirm NanoString results. MYB protein expression was analyzed by immunohistochemistry., Results: Of the 25 samples analyzed, 11/25 (44%) expressed a high degree of MYB 5'/3' imbalance and five of these samples were positive for at least one specific MYB-NFIB variant in our panel. MYB-NFIB variant detection on NanoString analysis was confirmed by direct cDNA sequencing. No clinical correlations were found to be associated with MYB fusion status., Conclusion: We conclude that the application of NanoString digital probe counting technology is well suited for the detection and quantification of MYB-NFIB fusion transcripts in archival ACC specimens.

ETV6 gene abnormalities are well described in tumor pathology. Many fusion partners of ETV6 have been reported in a variety of epithelial, mesenchymal, and hematological malignancies. In salivary gland tumor pathology, however, the ETV6-NTRK3 translocation is specific for (mammary analog) secretory carcinoma, and has not been documented in any other salivary tumor type. The present study comprised a clinical, histologic, and molecular analysis of 10 cases of secretory carcinoma, with typical morphology and immunoprofile harboring a novel ETV6-RET translocation.

Salivary gland neoplasms are a morphologically heterogenous group of lesions that are often diagnostically challenging. In recent years, considerable progress in salivary gland taxonomy has been reached by the discovery of tumor type-specific fusion oncogenes generated by chromosome translocations. This review describes the clinicopathologic features of a selected group of salivary gland carcinomas with a focus on their distinctive genomic characteristics. Mammary analog secretory carcinoma is a recently described entity characterized by a t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 fusion. Hyalinizing clear cell carcinoma is a low-grade tumor with infrequent nodal and distant metastasis, recently shown to harbor an EWSR1-ATF1 gene fusion. The CRTC1-MAML2 fusion gene resulting from a t(11;19)(q21;p13) translocation, is now known to be a feature of both low-grade and high-grade mucoepidermoid carcinomas associated with improved survival. A t(6;9)(q22-23;p23-34) translocation resulting in a MYB-NFIB gene fusion has been identified in the majority of adenoid cystic carcinomas. Polymorphous (low-grade) adenocarcinoma and cribriform adenocarcinoma of (minor) salivary gland origin are related entities with partly differing clinicopathologic and genomic profiles; they are the subject of an ongoing taxonomic debate. Polymorphous (low-grade) adenocarcinomas are characterized by hot spot point E710D mutations in the PRKD1 gene, whereas cribriform adenocarcinoma of (minor) salivary glands origin are characterized by translocations involving the PRKD1-3 genes. Salivary duct carcinoma (SDC) is a high-grade adenocarcinoma with morphologic and molecular features akin to invasive ductal carcinoma of the breast, including HER2 gene amplification, mutations of TP53, PIK3CA, and HRAS and loss or mutation of PTEN. Notably, a recurrent NCOA4-RET fusion has also been found in SDC. A subset of SDC with apocrine morphology is associated with overexpression of androgen receptors. As these genetic aberrations are recurrent they serve as powerful diagnostic tools in salivary gland tumor diagnosis, and therefore also in refinement of salivary gland cancer classification. Moreover, they are promising as prognostic biomarkers and targets of therapy.